Letter | Published:

Microglia-dependent synapse loss in type I interferon-mediated lupus

Nature volume 546, pages 539543 (22 June 2017) | Download Citation

Abstract

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis—collectively this is referred to as central nervous system (CNS) lupus1,2,3,4. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies5,6, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab7, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.

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Acknowledgements

We thank members of the M.C.C. and G.C.T. laboratories for helpful comments on experimental design and feedback on the manuscript; M. Tsokos, B. Volpe, P. Crow, B. Stevens and S. McCarroll for helpful discussions; E. M. Carroll for assistance and L. Prince-Wright for technical support; the HMS Rodent Histopathology core, and M. Ericsson and E. Benecchi from the HMS Electron Microscopy core; L. Konnikova and S. Snapper for advice and assistance with RNAscope; B. Caldarone at the Harvard NeuroDiscovery Center’s NeuroBehavior Laboratory Core for guidance; the Boston Children’s Hospital PCMM Optical Microscopy and flow cytometry cores and the Whitehead Institute Genome Technology Core; K. Holton from the HMS Bioinformatics core and S. Bradley for assistance with RNA-seq analysis, and C. Usher for help with editing the manuscript. This research was supported by the Alliance for Lupus Research (A.L.R.—332527); NIH (AI039246) and MedImmune LLC (M.C.C.), and by the NIH (AI42269) (G.C.T.). A.R.B. was supported by a NIH T32 training grant (AI74549) and the Jeffrey Modell Foundation.

Author information

Affiliations

  1. Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Allison R. Bialas
    • , Jessy Presumey
    • , Abhishek Das
    • , Cees E. van der Poel
    •  & Michael C. Carroll
  2. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    • Peter H. Lapchak
    •  & George C. Tsokos
  3. Laboratory for Lymphocyte Dynamics, The Rockefeller University, New York City, New York, USA

    • Luka Mesin
    •  & Gabriel Victora
  4. Department of Neuropathology, University of Magdeburg, Magdeburg, Germany

    • Christian Mawrin
  5. Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

    • Christian Mawrin
  6. Department of Cancer Biology, MedImmune LLC, Gaithersburg, Maryland 20878, USA

    • Ronald Herbst

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Contributions

A.R.B. designed and performed experiments and wrote the manuscript. J.P. assisted with flow cytometry and manuscript editing. A.D. assisted with bone marrow chimaeras and anti-IFNAR treatment. C.E.v.d.P. assisted with FACS purification of microglia, RNA-seq and manuscript editing. L.M. and G.V. helped with RNA-seq data acquisition and analysis. C.M. acquired samples and performed immunohistochemistry on tissue from patients with SLE. R.H. provided anti-IFNAR and isotype-control antibodies and advised on anti-IFNAR treatment. P.H.L. and G.C.T. provided MRL-lpr and control tissue and helpful feedback on the manuscript. M.C.C. advised on experimental design and assisted in manuscript preparation.

Competing interests

R.H. is an employee of MedImmune LLC. All other authors have no competing financial interests to declare.

Corresponding author

Correspondence to Michael C. Carroll.

Reviewer Information Nature thanks D. Hunt, R. Klein and M. Prinz for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature22821

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